Delirium is a disturbance in consciousness that typically results from an underlying physical condition. Patients suffering from delirium display changes in cognition (such as memory deficits, disorientation, and language or perceptual disturbances) that develop over a short period of time and tend to fluctuate during the course of the day.
The neurophysiological causes of delirium are not known in detail. The predominant neurochemical hypothesis for the origin of delirium focuses on underactivity of cholinergic neurotransmission in particular domains of the brain (see Trzepacz, Dement Geriatr Cogn Disord 10:330-334 (1999)). However, abnormalities in other neurotransmitters—such as serotonin, dopamine, gamma-aminobutryic acid, and glutamate—may also be involved in the development of delirium under particular conditions (see Flacker & Lipsitz, J Gerontol A Biol Sci Med Sci 54:B239-46 (1999)).
Cortisol, a glucocorticoid hormone secreted in response to ACTH (corticotropin), shows circadian rhythm variation, and further, is an important element in responsiveness to many physical and psychological stresses. It has been proposed that, with age, the cortisol regulatory system becomes hyperactivated in some individuals, resulting in hypercortisolemia. It has additionally been postulated that high levels of cortisol are neurotoxic, particularly in the hippocampus, a brain structure that is thought to be central to the processing and temporary storage of complex information and memory (see, e.g., Sapolsky et al., Ann. NY Acad. Sci. 746:294-304, 1994; Silva, Annu. Rev. Genet. 31:527-546, 1997; de Leon et al., J. Clin. Endocrinol & Metab. 82:3251, 1997).
The brain and CNS actions of cortisol and other glucocorticoids are not limited to neurotoxicity, however. In addition to influencing cerebral blood flow, oxygen consumption, and cerebral excitability, glucocorticoids have extensive effects on neurotransmitter function (see DeKloet et al., Handbook Neurochem 8:47-91 (1985)). These effects include inhibition of binding to central muscarinic cholinergic receptors, as well as modulation of serotonin turnover, hypothalamic dopamine balance, and suppression of beta-endorphin levels in the brain. The ability of glucocorticoids to perturb neurotransmitters involved in the pathogenesis of delirium suggests that disturbance of glucocorticoid regulation might play a role in delirium. However, while pathologically elevated glucocorticoid levels (due to adrenal dysfunction or ingestion of synthetic hormones) have been connected with the induction of delirium (see Stroudemire et al., Gen Hosp Psychiatry 18:196-202 (1996)), the relationship between physiological glucocorticoid levels and delirium remains unclear (for review see Flacker & Lipsitz, J Gerontol A Biol Sci Med Sci 54:B239-46 (1999)). Assessments of hypothalamic-pituitary-adrenal axis function in delirious patients by dexamethasone-suppression testing have been conflicting (see Koponen et al., Nord Psykiatr Tidsskr 43:203-207 (1987); McKeith, Br J Psychiatry 145:389-393 (1984); O'Keefe & Devline, Neuropsychobiology 30:153-156 (1994)). Furthermore, while some studies measuring glucocorticoid levels directly have found an association between delirium and persistent hypercortisolism (Gustafson et al., Cerebrovasc Dis 3:33-38 (1993)), other studies have failed to link the incidence of delirium with elevated cortisol levels (van der Mast et al., in Filippini ed., Recent Advances in Tryptophan Research, New York: Plenum Press, 93-96 (1996); McIntosh et al., Psychoneuroendocrinology 10:303-313 (1985)).
There has been no evidence prior to this invention, however, that a glucocorticoid receptor antagonist can be an effective treatment for delirium, especially in patients having cortisol levels that fall within a normal range. Many of the actions of cortisol are mediated by binding to the type I (mineralocorticoid) receptor, which is preferentially occupied, relative to the type II (glucocorticoid) receptor, at physiological cortisol levels. As cortisol levels increase, more glucocorticoid receptors are occupied and activated. Because cortisol plays an essential role in metabolism, inhibition of all cortisol-mediated activities, however, would be fatal. Therefore, antagonists that specifically prevent type II glucocorticoid receptor functions, but do not antagonize type I mineralocorticoid receptor functions are of particular use in this invention. Mifepristone (RU486) and similar antagonists are examples of this category of receptor antagonists.
The present inventors have determined that glucocorticoid receptor antagonists such as RU486 are effective agents for the specific treatment of delirium in patients with normal or decreased cortisol levels. The present invention therefore fulfills the need for an effective treatment for the symptoms of delirium by providing methods of administering glucocorticoid receptor antagonists to treat patients diagnosed with delirium.